Oroxylin A suppresses breast cancer-induced osteoclastogenesis and osteolysis as a natural RON inhibitor.

BACKGROUND: Malignant breast cancer cells trigger the over-activation of osteoclast precursor cells, leading to bone loss and severe pain. Targeted inhibition of osteoclast differentiation has emerged as an important strategy for treating bone syndromes induced by breast cancer. PURPOSE: The objective is to discover natural osteoclast inhibitor to treat osteoclastogenesis and bone destruction induced by breast cancer, and clarify the specific mechanisms. METHODS: Recepteur d'origine Nantais (RON) protein was employed to search the natural osteoclast inhibitor for breast cancer-induced osteoclastogenesis by molecular docking, molecular dynamics simulation and cellular thermal shift assay (CETSA). In the in vitro experiment, breast cancer MDA-MB-231 cell-conditioned medium (MDA-MB-231 CM) was used to induce osteoclastogenesis in murine bone marrow-derived macrophages (BMMs), aiming to elucidate the effects and mechanisms of the natural osteoclast inhibitor. In the in vivo model, MDA-MB-231 cells was injected into the mouse tibia to evaluate the therapeutic effect of drug on breast cancer-induced bone destruction. RESULTS: We discovered a significant increase in the expression of RON during MDA-MB-231 CM-induced osteoclast differentiation in vitro. Molecular docking analysis found that oroxylin A (OA), a flavonoid derived from the Chinese medicine Scutellaria baicalensis Georgi, showed binding ability with RON, while its impact and mechanism on breast cancer-induced osteoclastogenesis and osteolysis remains unclear. Molecular dynamics simulation and CETSA further revealed that OA bound directly to the RON protein, and it also decreased RON expression in breast cancer CM-induced osteoclastogenesis. Correspondingly, OA suppressed the MDA-MB-231 CM-induced osteoclastogenesis and bone resorption in vitro. The downstream signals of RON including Src and NFATc1, as well as the osteoclast-specific genes, were downregulated by OA. Of interesting, the suppressive effect of OA on osteoclastogenesis induced by MDA-MB-231 CM was abolished after RON was knocked down by the specific RON-siRNA, this further confirmed that OA showed inhibitory effects on osteoclasts through targeting RON. In addition, we found that OA attenuated MDA-MB-231 cell-induced osteolysis and reduced the number of osteoclasts in vivo. CONCLUSION: Our results indicate that OA acts as a natural RON inhibitor to suppress breast cancer-induced osteoclastogenesis and osteolysis. This provides new strategy for treating breast cancer-induced bone destruction and related syndromes.

Excitotoxic Storms of Ischemic Stroke: A Non-neuronal Perspective.

Numerous neurological disorders share a fatal pathologic process known as glutamate excitotoxicity. Among which, ischemic stroke is the major cause of mortality and disability worldwide. For a long time, the main idea of developing anti-excitotoxic neuroprotective agents was to block glutamate receptors. Despite this, there has been little successful clinical translation to date. After decades of "neuron-centered" views, a growing number of studies have recently revealed the importance of non-neuronal cells. Glial cells, cerebral microvascular endothelial cells, blood cells, and so forth are extensively engaged in glutamate synthesis, release, reuptake, and metabolism. They also express functional glutamate receptors and can listen and respond for fast synaptic transmission. This broadens the thoughts of developing excitotoxicity antagonists. In this review, the critical contribution of non-neuronal cells in glutamate excitotoxicity during ischemic stroke will be emphasized in detail, and the latest research progress as well as corresponding therapeutic strategies will be updated at length, aiming to reconceptualize glutamate excitotoxicity in a non-neuronal perspective.

Novel nano-drug delivery system for natural products and their application.

The development of natural products for potential new drugs faces obstacles such as unknown mechanisms, poor solubility, and limited bioavailability, which limit the broadened applicability of natural products. Therefore, there is a need for advanced pharmaceutical formulations of active compounds or natural products. In recent years, novel nano-drug delivery systems (NDDS) for natural products, including nanosuspensions, nanoliposomes, micelle, microemulsions/self-microemulsions, nanocapsules, and solid lipid nanoparticles, have been developed to improve solubility, bioavailability, and tissue distribution as well as for prolonged retention and enhanced permeation. Here, we updated the NDDS delivery systems used for natural products with the potential enhancement in therapeutic efficiency observed with nano-delivery systems.

Causal relationship between worry, tension, insomnia, sensitivity to environmental stress and adversity, and erectile dysfunction: a study using Mendelian randomization.

BACKGROUND: This study aims to investigate the causal relationship between erectile dysfunction (ED) and psychological states including worry, tension, insomnia, sensitivity to environmental stress and adversity (SESA). METHOD: This study the used two-sample bi-directional Mendelian randomization (MR) method. The study data was obtained from a pooled dataset of genome-wide association studies (GWAS). The bi-directional MR analysis was performed using inverse variance weighting, weighted median method, and MR-Egger regression analysis to assess the causality between ED and psychological states including worry, tension, insomnia, SESA in terms of odd ratios (OR). The study tested for heterogeneity using the Cochran Q method and for multiple validity using the MR-Egger and MR-PRESSO methods. RESULTS: In forward MR analysis correlating worry, tension, insomnia, and SESA as exposures, no causal relationship was found between worry or tension and ED (p < 0.05). However, insomnia (p = 0.001, OR = 3.441, 95%CI = 1.593-7.435) and SESA (p = 0.004, OR = 1.804, 95%CI = 1.203-2.701) were found to have a significant causal effect on ED risk. The reverse MR analysis with ED as the exposure did not show any significant correlation (all p > 0.05). CONCLUSION: Individuals with insomnia and SESA are at higher risk for developing ED. Clinical evaluation should be more thorough for these individuals. Insomnia can be treated simultaneously with psychological counseling to reduce the risk of ED. In addition, there is no evidence to suggest that worry and tension increase the risk of ED.

Erratum: Author correction to 'Herbal formula BaWeiBaiDuSan alleviates polymicrobial sepsis-induced liver injury via increasing the gut microbiota Lactobacillus johnsonii and regulating macrophage anti-inflammatory activity in mice' [Acta Pharmaceutica Sinica B 13 (2023) 1164-1179].

[This corrects the article DOI: 10.1016/j.apsb.2022.10.016.].

Age-Related Alterations in Immune Function and Inflammation: Focus on Ischemic Stroke.

The aging of the global population poses significant scientific challenges. Moreover, the biological process of aging is the most significant risk factor for most chronic illnesses; therefore, understanding the molecular and cellular mechanisms underlying these aging-related challenges is crucial for extending the healthy lifespan of older individuals. Preventing brain aging remains a priority public health goal, and integrative and comprehensive aging analyses have revealed that immunosenescence is a potential cause of age-related brain damage and disease (e.g., stroke). Importantly, the neuroinflammatory and immune systems present two-way contact and thus can affect each other. Emerging evidence supports the numerous effects of immunosenescence- and inflammation-mediated immunity in neurologically injured brains. In this study, we briefly outline how aging alters the pathophysiology and transcriptional amplitude in patients who experienced stroke and then discuss how the immune system and its cellular components and molecular mechanisms are affected by age after stroke. Finally, we highlight emerging interventions with the potential to slow down or reduce aging and prevent stroke onset.

Clinical progress of anti-angiogenic targeted therapy and combination therapy for gastric cancer.

The incidence of gastric cancer is increasing year by year. Most gastric cancers are already in the advanced stage with poor prognosis when diagnosed, which means the current treatment is not satisfactory. Angiogenesis is an important link in the occurrence and development of tumors, and there are multiple anti-angiogenesis targeted therapies. To comprehensively evaluate the efficacy and safety of anti-angiogenic targeted drugs alone and in combination against gastric cancer, we systematically searched and sorted out relevant literature. In this review, we summarized the efficacy and safety of Ramucirumab, Bevacizumab, Apatinib, Fruquintinib, Sorafenib, Sunitinib, Pazopanib on gastric cancer when used alone or in combination based on prospective clinical trials reported in the literature, and sorted response biomarkers. We also summarized the challenges faced by anti-angiogenesis therapy for gastric cancer and available solutions. Finally, the characteristics of the current clinical research are summarized and suggestions and prospects are raised. This review will serve as a good reference for the clinical research of anti-angiogenic targeted drugs in the treatment of gastric cancer.

Glycyrrhizic acid modified Poria cocos polyscaccharide carbon dots dissolving microneedles for methotrexate delivery to treat rheumatoid arthritis.

Introduction: Rheumatoid arthritis is an autoimmune disease characterized by chronic joint inflammation. Methotrexate is one of the most effective drugs for rheumatoid arthritis, but the adverse reactions caused by oral methotrexate greatly limit its clinical application. Transdermal drug delivery system is an ideal alternative to oral methotrexate by absorbing drugs into the human body through the skin. However, methotrexate in the existing methotrexate microneedles is mostly used alone, and there are few reports of combined use with other anti-inflammatory drugs. Methods: In this study, glycyrrhizic acid was first modified onto carbon dots, and then methotrexate was loaded to construct a nano-drug delivery system with fluorescence and dual anti-inflammatory effects. Then hyaluronic acid was combined with nano-drug delivery system to prepare biodegradable soluble microneedles for transdermal drug delivery of rheumatoid arthritis. The prepared nano-drug delivery system was characterized by transmission electron microscopy, fluorescence spectroscopy, laser nanoparticle size analyzer, ultraviolet-visible absorption spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimeter and nuclear magnetic resonance spectrometer. The results showed that glycyrrhizic acid and methotrexate were successfully loaded on carbon dots, and the drug loading of methotrexate was 49.09%. The inflammatory cell model was constructed by lipopolysaccharide-induced RAW264.7 cells. In vitro cell experiments were used to explore the inhibitory effect of the constructed nano-drug delivery system on the secretion of inflammatory factors by macrophages and the cell imaging ability. The drug loading, skin penetration ability, in vitro transdermal delivery and in vivo dissolution characteristics of the prepared microneedles were investigated. The rat model of rheumatoid arthritis was induced by Freund's complete adjuvant. Results: The results of in vivo animal experiments showed that the soluble microneedles of the nano drug delivery system designed and prepared in this study could significantly inhibit the secretion of pro-inflammatory cytokines and had a significant therapeutic effect on arthritis. Discussion: The prepared glycyrrhizic acid-carbon dots-methotrexate soluble microneedle provides a feasible solution for the treatment of Rheumatoid arthritis.

Combinational study with network pharmacology, molecular docking and preliminary experiments on exploring common mechanisms underlying the effects of weijing decoction on various pulmonary diseases.

Objective: 'Homotherapy for heteropathy' is a theory by which different diseases with similar pathogenesis can be treated with one Chinese formula. We aimed to explore the key components and core targets of Weijing decoction (WJD) in treating various lung diseases, namely, pneumonia, chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), pulmonary fibrosis, pulmonary tuberculosis and non-small cell lung cancer (NSCLC), via network pharmacology, molecular docking and some experiments. Significance: This is the first study on the mechanism of WJD in treating various lung diseases by 'homotherapy for heteropathy'. This study is helpful for the transformation of TCM formula and development of new drugs. Methods: Active components and therapeutic targets of WJD were obtained via TCMSP and UniProt databases. Targets of the six pulmonary diseases were harvested from the GeneCards TTD, DisGeNet, UniProt and OMIM databases. Drug-disease intersection targets, corresponding Venn diagrams, herb-component-target networks and protein-protein interaction networks were established. Furthermore, GO biological function and KEGG enrichment analysis were completed. Moreover, the binding activity between main compounds and core targets was measured through molecular docking. Finally, the xenograft NSCLC mouse model was established. Immune responses were evaluated by flow cytometry and mRNA expression levels of critical targets were measured by real-time PCR. Results: JUN, CASP3 and PTGS2 were the most critical targets in six pulmonary diseases. The active compounds beta-sitosterol, tricin and stigmasterol stably bound to many active sites on target proteins. WJD had extensive pharmacological regulation, involving pathways related to cancer, inflammation, infection, hypoxia, immunity and so on. Conclusions: Effects of WJD against various lung diseases involve lots of compounds, targets and pathways. These findings will facilitate further research as well as clinical application of WJD.

Tumor-microenvironment-responsive poly-prodrug encapsulated semiconducting polymer nanosystem for phototherapy-boosted chemotherapy.

Phototherapy-induced hypoxia in the tumor microenvironment (TME) is responsible for diminished therapeutic efficacy. Designing an intelligent nanosystem capable of responding to hypoxia for TME-responsive drug delivery will, to some extent, improve the therapeutic efficacy and reduce side effects. Semiconducting polymers with high photothermal conversion efficiency and photostability have tremendous potential as phototheranostics. In this paper, hypoxia-activatable tirapazamine (TPZ) was conjugated onto poly(ethylene glycol) to form a pH-sensitive poly-prodrug, PEG-TPZ, that can be triggered by the low acidity of the TME to cleave the acylamide bond for controllable drug release. PEG-TPZ was then used to encapsulate a semiconducting polymer (TDPP) for NIR-II-fluorescence-imaging-guided synergistic therapy. The reactive oxygen species (ROS) generation and ultrahigh photothermal conversion efficiency (∼58.6%) of the TDPP@PEG-TPZ NPs leads to the destruction of the tumor blood vessels, thus further activating the hypoxia-induced chemotherapy of TPZ. As a result, effective tumor regression was achieved after laser irradiation.

Sinomenine hydrochloride bidirectionally inhibits progression of tumor and autoimmune diseases by regulating AMPK pathway.

BACKGROUND: Chronic diseases such as tumors and autoimmune disorders are closely linked to metabolism and immunity and require conflicting treatment methods. AMPK can regulate cell growth and inflammation through energy metabolism. Sinomenine is a compound extracted from the traditional Chinese herb sinomenium acutum (Thunb.) Rehd. et Wils. It has been used to treat NSCLC (non-small-cell lung cancer) and RA (rheumatoid arthritis) in some studies, but with limited understanding of its mechanisms. OBJECTIVE: This study aims to examine the inhibitory effect of sinomenine hydrochloride (SH) on NSCLC and RA and to understand the underlying joint mechanisms. RESULTS: The results indicate that SH has a cytotoxic effect specifically on tumor cells, but not on normal cells. SH was found to induce cell apoptosis by activating the AMPK-mTOR pathway. Additionally, in autoimmune disease cell models, SH was shown to reduce the growth of RA-FLS cells by inhibiting the phosphorylation of AMPK, while having no effect on normal macrophages. Moreover, in vivo studies also showed that SH could reduce the production of pro-inflammatory cytokines such as TNF-α, IL-1ß, and IL-6 and slow the development of adjuvant arthritis in rats. Furthermore, SH was found to significantly suppress tumor growth in a tumor xenograft experiment in mice. CONCLUSIONS: This study provides new insights into the treatment of tumors and autoimmune diseases by demonstrating that SH can selectively inhibit the growth of NSCLC cells and the progression of RA through activation of the AMPK pathway.

A novel quantification method of lung fibrosis based on Micro-CT images developed with the optimized pulmonary fibrosis mice model induced by bleomycin.

Background and aims: Idiopathic pulmonary fibrosis (IPF) is a fibrosing lung disease with unknown etiology, leading to cough and dyspnoea, which is also one of the most common sequelae affecting the quality of life of COVID-19 survivors. There is no cure for IPF patients. We aim to develop a reliable IPF animal model with quantification of fibrosis based on Micro-Computer Tomography (micro-CT) images for the new drug discovery, because different bleomycin administration routes, doses, and intervals are reported in the literature, and there is no quantitative assessment of pulmonary fibrosis based on micro-CT images in animal studies. Methods: We compared three dosages (1.25 mg/kg, 2.5 mg/kg, and 5 mg/kg) of intratracheal bleomycin administration and experiment intervals (14 and 21 days) in C57BL/6 mice by investigating survival rates, pulmonary histopathology, micro-CT, peripheral CD4+ & CD8+ cells, and cytokines. Moreover, a simple and reliable new method was developed for scoring fibrosis in live mice based on Micro-CT images by using Image J software, which transfers the dark sections in pulmonary Micro-CT images to light colors on a black background. Results: The levels of hydroxyproline, inflammation cytokine, fibrotic pathological changes, and collagen deposition in the lungs of mice were bleomycin dose-dependent and time-dependent as well as the body weight loss. Based on the above results, the mice model at 21 days after being given bleomycin at 1.25 mg/kg has optimal pulmonary fibrosis with a high survival rate and low toxicity. There is a significant decrease in the light area (gray value at 9.86 ± 0.72) in the BLM mice, indicating that a significant decrease in the alveolar air area was observed in BLM injured mice compared to normal groups (###p < 0.001), while the Pirfenidone administration increased the light area (gray value) to 21.71 ± 2.95 which is close to the value observed in the normal mice (gray value at 23.23 ± 1.66), which is consistent with the protein levels of Col1A1, and α-SMA. Notably, the standard deviations for the consecutive six images of each group indicate the precision of this developed quantitation method for the micro-CT image taken at the fifth rib of each mouse. Conclusion: Provided a quantifying method for Micro-CT images in an optimal and repeatable pulmonary fibrosis mice model for exploring novel therapeutic interventions.

Herbal formula BaWeiBaiDuSan alleviates polymicrobial sepsis-induced liver injury via increasing the gut microbiota Lactobacillus johnsonii and regulating macrophage anti-inflammatory activity in mice.

Sepsis-induced liver injury (SILI) is an important cause of septicemia deaths. BaWeiBaiDuSan (BWBDS) was extracted from a formula of Panax ginseng C. A. Meyer, Lilium brownie F. E. Brown ex Miellez var. viridulum Baker, Polygonatum sibiricum Delar. ex Redoute, Lonicera japonica Thunb., Hippophae rhamnoides Linn., Amygdalus Communis Vas, Platycodon grandiflorus (Jacq.) A. DC., and Cortex Phelloderdri. Herein, we investigated whether the BWBDS treatment could reverse SILI by the mechanism of modulating gut microbiota. BWBDS protected mice against SILI, which was associated with promoting macrophage anti-inflammatory activity and enhancing intestinal integrity. BWBDS selectively promoted the growth of Lactobacillus johnsonii (L. johnsonii) in cecal ligation and puncture treated mice. Fecal microbiota transplantation treatment indicated that gut bacteria correlated with sepsis and was required for BWBDS anti-sepsis effects. Notably, L. johnsonii significantly reduced SILI by promoting macrophage anti-inflammatory activity, increasing interleukin-10+ M2 macrophage production and enhancing intestinal integrity. Furthermore, heat inactivation L. johnsonii (HI-L. johnsonii) treatment promoted macrophage anti-inflammatory activity and alleviated SILI. Our findings revealed BWBDS and gut microbiota L. johnsonii as novel prebiotic and probiotic that may be used to treat SILI. The potential underlying mechanism was at least in part, via L. johnsonii-dependent immune regulation and interleukin-10+ M2 macrophage production.

Traditional Herbal Medicine: A Potential Therapeutic Approach for Adjuvant Treatment of Non-small Cell Lung Cancer in the Future.

Lung carcinoma is the primary reason for cancer-associated mortality, and it exhibits the highest mortality and incidence in developed and developing countries. Non-small cell lung cancer (NSCLC) and SCLC are the 2 main types of lung cancer, with NSCLC contributing to 85% of all lung carcinoma cases. Conventional treatment mainly involves surgery, chemoradiotherapy, and immunotherapy, but has a dismal prognosis for many patients. Therefore, identifying an effective adjuvant therapy is urgent. Historically, traditional herbal medicine has been an essential part of complementary and alternative medicine, due to its numerous targets, few side effects and substantial therapeutic benefits. In China and other East Asian countries, traditional herbal medicine is increasingly popular, and is highly accepted by patients as a clinical adjuvant therapy. Numerous studies have reported that herbal extracts and prescription medications are effective at combating tumors. It emphasizes that, by mainly regulating the P13K/AKT signaling pathway, the Wnt signaling pathway, and the NF-κB signaling pathway, herbal medicine induces apoptosis and inhibits the proliferation and migration of tumor cells. The present review discusses the anti-NSCLC mechanisms of herbal medicines and provides options for future adjuvant therapy in patients with NSCLC.

Bioengineered polyester nanoparticles for the synergistic treatment of androgenic alopecia via the suppression of 5α-reductase and knockdown of androgen receptor.

Androgenic alopecia (AGA) is a common disease that negatively affects patients' physical and mental health. AGA can be treated with drugs that improve the perifollicular microenvironment, such as 5α-reductase inhibitors (e.g., dutasteride [DUT]), androgen receptor blockers, and minoxidil. However, the efficacy of these treatments is limited. Therefore, this study aimed to show that nanoparticles are effective as stable carriers with high curative benefits and little adverse effects. The in vitro study showed that PLGA-DUT/siAR@DPCM NPs could deliver both DUT and siAR to dermal papilla cells. They could successfully suppress 5α-reductase and knock down androgen receptor, respectively, and thereby promote cell proliferation. In the in vivo study, PLGA-DUT/siAR@DPCM NPs showed a significant therapeutic effect in an AGA mouse model. They successfully penetrated the stratum corneum and showed a clear targeting effect on hair follicles and surrounding tissues. PLGA-DUT/siAR@DPCM NPs could enable the targeted delivery of DUT and siAR through percutaneous penetration, enhancing phagocytosis and decreasing adverse effects. Thus, they have great potential in the clinical treatment of AGA.

Down-regulating Nrf2 by tangeretin reverses multiple drug resistance to both chemotherapy and EGFR tyrosine kinase inhibitors in lung cancer.

Multiple drug resistance (MDR) is the major obstacle for both chemotherapy and molecular-targeted therapy for cancer, which is mainly caused by overexpression of ABC transporters or genetic mutation of drug targets. Based on previous studies, we hypothesized that ROS/Nrf2 is the common target for overcoming acquired drug resistance to both targeted therapy and chemotherapy treatments. In this study, we firstly proved that the levels of ROS and Nrf2 were remarkably up-regulated in both H1975 (Gefitinib-resistant lung cancer cells with T790M) and A549/T (paclitaxel-resistant) cells, which is consistent with the clinical database analysis results of lung cancer patients that Nrf2 expression level is negatively related to survival rate. Nrf2 Knockdown with siRNA or tangeretin (TG, a flavonoid isolated from citrus peels) inhibited the MDR cell growth by suppressing the Nrf2 pathway, and efficiently enhanced the anti-tumor effects of paclitaxel and AZD9291 (the third generation of TKI) in A549/T or H1975, respectively. Moreover, TG sensitized A549/T cells-derived xenografts to paclitaxel via inhibiting Nrf2 and its downstream target P-gp, leading to an increased paclitaxel concentration in tumors. Collectively, targeting Nrf2 to enhance ROS may be a common target for overcoming the acquired drug resistance and enhancing the therapeutic effects of chemotherapy and molecular-targeted therapy.

The key role of sphingolipid metabolism in cancer: New therapeutic targets, diagnostic and prognostic values, and anti-tumor immunotherapy resistance.

Biologically active sphingolipids are closely related to the growth, differentiation, aging, and apoptosis of cancer cells. Some sphingolipids, such as ceramides, are favorable metabolites in the sphingolipid metabolic pathway, usually mediating antiproliferative responses, through inhibiting cancer cell growth and migration, as well as inducing autophagy and apoptosis. However, other sphingolipids, such as S1P, play the opposite role, which induces cancer cell transformation, migration and growth and promotes drug resistance. There are also other sphingolipids, as well as enzymes, played potentially critical roles in cancer physiology and therapeutics. This review aimed to explore the important roles of sphingolipid metabolism in cancer. In this article, we summarized the role and value of sphingolipid metabolism in cancer, including the distribution of sphingolipids, the functions, and their relevance to cancer diagnosis and prognosis. We also summarized the known and potential antitumor targets present in sphingolipid metabolism, analyzed the correlation between sphingolipid metabolism and tumor immunity, and summarize the antitumor effects of natural compounds based on sphingolipids. Through the analysis and summary of sphingolipid antitumor therapeutic targets and immune correlation, we aim to provide ideas for the development of new antitumor drugs, exploration of new therapeutic means for tumors, and study of immunotherapy resistance mechanisms.

Immune regulation mediated by JAK/STAT signaling pathway in hemocytes of Pacific white shrimps, Litopenaeus vannamei stimulated by lipopolysaccharide.

To understand the regulatory mechanism of Janus kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signaling pathway on the immune system of the Pacific white shrimp, Litopenaeus vannamei, RNA interference technique was used to investigate the effects of JAK/STAT signaling pathway on the immune response of hemocyte in Litopenaeus vannamei stimulated by lipopolysaccharide (LPS). The results showed that 1) after 6 h of LPS stimulation, the expression levels of immune genes in hemocyte were significantly up-regulated (P < 0.05), the immune defense ability (hemocyte number, phagocytosis rate, hemagglutination activity, bacteriolytic activity, antibacterial activity, prophenoloxidase system activity) and the hemocyte antioxidant ability were significantly higher than the control group, especially at 12 h. 2) After 48 h of STAT gene interference, the expression levels of immune genes in hemocytes were significantly down-regulated, and the immune defense ability (hemocyte count, phagocytosis rate, plasma agglutination activity, lysozyme activity, antibacterial activity, proPO system activity) and the antioxidant ability were reduced and significantly lower than control. Concurrently, after LPS stimulation, the immune indexes were significantly up-regulated at 12 h to the maximum but was still lower the undisturbed LPS group. These results indicate that JAK/STAT signaling pathway is involved in the immune regulation mechanism of L. vannamei against LPS stimulation through positive regulation of cellular immune and humoral immune. These results provide a basis for further research on the role and status of JAK/STAT signaling pathway in the immune defense of crustaceans.

Targeting Mutant Kirsten Rat Sarcoma Viral Oncogene Homolog in Non-Small Cell Lung Cancer: Current Difficulties, Integrative Treatments and Future Perspectives.

In the past few decades, several gene mutations, including the anaplastic lymphoma kinase, epidermal growth factor receptor, ROS proto-oncogene 1 and rat sarcoma viral oncogene homolog (RAS), have been discovered in non-small cell lung cancer (NSCLC). Kirsten rat sarcoma viral oncogene homolog (KRAS) is the isoform most frequently altered in RAS-mutated NSCLC cases. Due to the structural and biochemical characteristics of the KRAS protein, effective approaches to treating KRAS-mutant NSCLC still remain elusive. Extensive recent research on KRAS-mutant inhibitors has made a breakthrough in identifying the covalent KRASG12C inhibitor as an effective agent for the treatment of NSCLC. This review mainly concentrated on introducing new covalent KRASG12C inhibitors like sotorasib (AMG 510) and adagrasib (MRTX 849); summarizing inhibitors targeting the KRAS-related upstream and downstream effectors in RAF/MEK/ERK pathway and PI3K/AKT/mTOR pathway; exploring the efficacy of immunotherapy and certain emerging immune-related therapeutics such as adoptive cell therapy and cancer vaccines. These inhibitors are being investigated in clinical trials and have exhibited promising effects. On the other hand, naturally extracted compounds, which have exhibited safe and effective properties in treating KRAS-mutant NSCLC through suppressing the MAPK and PI3K/AKT/mTOR signaling pathways, as well as through decreasing PD-L1 expression in preclinical studies, could be expected to enter into clinical studies. Finally, in order to confront the matter of drug resistance, the ongoing clinical trials in combination treatment strategies were summarized herein.

Effect of acupuncture treatment on dysphagia caused by pseudobulbar paralysis after stroke: a systematic review and meta-analysis.

BACKGROUND: The efficacy of acupuncture in the treatment of dysphagia caused by pseudobulbar paralysis after stroke is lack of evidence-based medicine. Our objective was to synthesize the efficacy of acupuncture in treating dysphagia caused by pseudobulbar paralysis after stroke. METHODS: A comprehensive literature search was performed in 9 databases [PubMed, Web of Science, Embase, Cochrane, Chinese BioMedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), WanFang Data, Chinese Science and Technology Periodicals database (VIP), and Open Grey online database] to screen eligible randomized controlled studies that evaluated the effect of acupuncture in dysphagia caused by pseudobulbar paralysis after stroke. The search time limit is from establishing the database to October 1, 2020. The random-effects model was used to calculate the significant effect size. RESULTS: A total of 7 studies comprising 637 participants were included in our meta-analysis. The results showed that compared with rehabilitation, acupuncture had a significant effect on improving dysphagia caused by pseudobulbar paralysis after stroke [the significant effective size: risk ratio (RR)sig =1.51; 95% confidence interval (CI): 1.30-1.75; I2=0%]. In the subgroup analyses, the RRsig of acupuncture + rehabilitation vs. rehabilitation was 1.56 (95% CI: 1.30-1.87; I2=0%), and the RRsig of acupuncture vs. rehabilitation was 1.38 (95% CI: 1.08-1.76; I2=0.8%). DISCUSSION: Acupuncture can be used as an effective treatment for dysphagia caused by pseudobulbar paralysis after stroke. Acupuncture combined with rehabilitation therapy has better effects.